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Liu X, Zhang J, Yi T, Li H, Tang X, Liu D, Wu D, Li Y. Decoding tumor angiogenesis: pathways, mechanisms, and future directions in anti-cancer strategies. Biomark Res 2025; 13:62. [PMID: 40251641 PMCID: PMC12007322 DOI: 10.1186/s40364-025-00779-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 04/13/2025] [Indexed: 04/20/2025] Open
Abstract
Angiogenesis, a crucial process in tumor growth and metastasis, necessitates targeted therapeutic intervention. This review reviews the latest knowledge of anti-angiogenesis targets in tumors, with emphasis on the molecular mechanisms and signaling pathways that regulate this process. We emphasize the tumor microenvironment's role in angiogenesis, examine endothelial cell metabolic changes, and evaluated potential therapeutic strategies targeting the tumor vascular system. At the same time, we analyzed the signaling pathway and molecular mechanism of tumor angiogenesis in detail. In addition, this paper also looks at the development trend of tumor anti-angiogenesis drugs, including their future development direction and challenges, aiming to provide prospective insight into the development of this field. Despite their potential, anti-angiogenic therapies encounter challenges like drug resistance and side effects, necessitating ongoing research to enhance cancer treatment strategies and the efficacy of these therapies.
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Affiliation(s)
- Xueru Liu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Juan Zhang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Ting Yi
- Department of Trauma Center, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Hui Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Xing Tang
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Dan Liu
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China
| | - Daichao Wu
- Laboratory of Structural Immunology, Department of Hepatopancreatobiliary Surgery, Hengyang Medical School, The First Affiliated Hospital, University of South China, Hengyang, 421001, Hunan, China.
| | - Yukun Li
- Department of Assisted Reproductive Centre, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412000, Hunan, China.
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Vatankhah A, Moghaddam SH, Afshari S, Afshari AR, Kesharwani P, Sahebkar A. Recent update on anti-tumor mechanisms of valproic acid in glioblastoma multiforme. Pathol Res Pract 2024; 263:155636. [PMID: 39395298 DOI: 10.1016/j.prp.2024.155636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/30/2024] [Accepted: 10/02/2024] [Indexed: 10/14/2024]
Abstract
Glioblastoma multiforme (GBM) is a malignant tumor of the brain that is considered to be incurable. Currently, surgical removal of tumors, chemotherapy with temozolomide, and radiation treatment remain established options for treatment. Nevertheless, the prognosis of those with GBM continues to be poor owing to the inherent characteristics of tumor growth and spread, as well as the resistance to treatment. To effectively deal with the present circumstances, it is vital to do extensive study to understand GBM thoroughly. The following piece provides a concise overview of the most recent advancements in using valproic acid, an antiseizure medication licensed by the FDA, for treating GBM. In this review, we outline the most recent developments of valproic acid in treating GBM, as well as its fundamental mechanisms and practical consequences. Our goal is to provide a greater understanding of the clinical use of valproic acid as a potential therapeutic agent for GBM.
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Affiliation(s)
- Abulfazl Vatankhah
- School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | | | - Sadaf Afshari
- Student Research Committee, Faculty of Dentistry, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir R Afshari
- Department of Basic Sciences, Faculty of Medicine, Mashhad Medical Sciences, Islamic Azad University, Mashhad, Iran; Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran; Department of Physiology and Pharmacology, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran.
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Amirhossein Sahebkar
- Center for Global health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Addisu S, Bekele A, Seifu D, Assefa M, Gemechu T, Hoenerhoff MJ, Merajver SD. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor A (VEGF-A) expressions in Ethiopian female breast cancer and their association with histopathologic features. PLoS One 2024; 19:e0308411. [PMID: 39405290 PMCID: PMC11478813 DOI: 10.1371/journal.pone.0308411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 07/22/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGF) play important role in breast tumor growth, invasion, metastasis, patient survival and drug resistance. The aim of this study was to evaluate the protein expression status of EGFR and VEGF-A, as well as their association with hormone receptor status and histopathological characteristics in the invasive type of female breast cancer among Ethiopians. METHOD The primary breast tumor tissues were obtained from 85 Ethiopian invasive breast cancer cases that underwent modified radical mastectomy (MRM) from June 2014 to June 2015. Their FFPE blocks were analyzed for EGFR and VEGF protein expressions using immunohistochemical techniques. The expressions were also correlated with histopathologic features. RESULT Epidermal growth factor receptor over-expression was observed in 22% of the tumor samples. VEGF-A expression was negative in 13.41%, low in 63.41%, moderate in 20.73%, and high in 2.44%. EGFR expression, but not VEGF-A, showed a significant inverse correlation with both estrogen receptor (ER) (P = 0.01) and progesterone receptor (PR) statuses (P = 0.04). EGFR and VEGF expressions did not show significant association with tumor size, grade, lymph node status or age at diagnosis. CONCLUSION Epidermal growth factor receptor expression was most likely associated with ER and PR negative tumors. Assessments of multiple molecular markers aid to understand the biological behavior of the disease in Ethiopian population. It might also help to predict which group of patients might get more benefit from the selected treatment strategies and which are not.
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Affiliation(s)
- Sisay Addisu
- Department of Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Abebe Bekele
- Department of Surgery, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Daniel Seifu
- Department of Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Mathewos Assefa
- Department of Internal Medicine, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Tufa Gemechu
- Department of Pathology, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Mark J. Hoenerhoff
- In Vivo Animal Core, Unit for Laboratory Animal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
| | - Sofia D. Merajver
- Division of Hematology and Oncology, Department of Internal Medicine, University of Michigan Rogel Cancer Center, Ann Arbor, Michigan, United States of America
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Jasim SA, Farber IM, Noraldeen SAM, Bansal P, Alsaab HO, Abdullaev B, Alkhafaji AT, Alawadi AH, Hamzah HF, Mohammed BA. Incorporation of immunotherapies and nanomedicine to better normalize angiogenesis-based cancer treatment. Microvasc Res 2024; 154:104691. [PMID: 38703993 DOI: 10.1016/j.mvr.2024.104691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/11/2024] [Accepted: 04/27/2024] [Indexed: 05/06/2024]
Abstract
Neoadjuvant targeting of tumor angiogenesis has been developed and approved for the treatment of malignant tumors. However, vascular disruption leads to tumor hypoxia, which exacerbates the treatment process and causes drug resistance. In addition, successful delivery of therapeutic agents and efficacy of radiotherapy require normal vascular networks and sufficient oxygen, which complete tumor vasculopathy hinders their efficacy. In view of this controversy, an optimal dose of FDA-approved anti-angiogenic agents and combination with other therapies, such as immunotherapy and the use of nanocarrier-mediated targeted therapy, could improve therapeutic regimens, reduce the need for administration of high doses of chemotherapeutic agents and subsequently reduce side effects. Here, we review the mechanism of anti-angiogenic agents, highlight the challenges of existing therapies, and present how the combination of immunotherapies and nanomedicine could improve angiogenesis-based tumor treatment.
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Affiliation(s)
| | - Irina M Farber
- Department of children's diseases of the F. Filatov clinical institute of children's health, I. M. Sechenov First Moscow State Medical University of Health of Russian Federation (Sechenov University), Moscow, Russia
| | | | - Pooja Bansal
- Department of Biotechnology and Genetics, Jain (Deemed-to-be) University, Bengaluru, Karnataka 560069, India; Department of Allied Healthcare and Sciences, Vivekananda Global University, Jaipur, Rajasthan 303012, India
| | - Hashem O Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, Taif University, Taif 21944, Saudi Arabia
| | - Bekhzod Abdullaev
- Research Department of Biotechnology, New Uzbekistan University, Mustaqillik Avenue 54, Tashkent 100007, Uzbekistan; Department of Oncology, School of Medicine, Central Asian University, Milliy Bog Street 264, Tashkent 111221, Uzbekistan..
| | | | - Ahmed Hussien Alawadi
- College of Technical Engineering, the Islamic University, Najaf, Iraq; College of Technical Engineering, the Islamic University of Al Diwaniyah, Qadisiyyah, Iraq; College of Technical Engineering, the Islamic University of Babylon, Babylon, Iraq
| | - Hamza Fadhel Hamzah
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
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Aljohani AKB, El Zaloa WAZ, Alswah M, Seleem MA, Elsebaei MM, Bayoumi AH, El-Morsy AM, Almaghrabi M, Awaji AA, Hammad A, Alsulaimany M, Ahmed HEA. Development of Novel Class of Phenylpyrazolo[3,4- d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies. Int J Mol Sci 2023; 24:15026. [PMID: 37834474 PMCID: PMC10573254 DOI: 10.3390/ijms241915026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/15/2023] Open
Abstract
Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3-24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.
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Affiliation(s)
- Ahmed K. B. Aljohani
- Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia; (A.K.B.A.); (M.A.); (M.A.)
| | - Waheed Ali Zaki El Zaloa
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt (M.A.S.); (M.M.E.); (A.H.B.); (A.M.E.-M.); (A.H.)
| | - Mohamed Alswah
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt (M.A.S.); (M.M.E.); (A.H.B.); (A.M.E.-M.); (A.H.)
| | - Mohamed A. Seleem
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt (M.A.S.); (M.M.E.); (A.H.B.); (A.M.E.-M.); (A.H.)
| | - Mohamed M. Elsebaei
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt (M.A.S.); (M.M.E.); (A.H.B.); (A.M.E.-M.); (A.H.)
| | - Ashraf H. Bayoumi
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt (M.A.S.); (M.M.E.); (A.H.B.); (A.M.E.-M.); (A.H.)
| | - Ahmed M. El-Morsy
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt (M.A.S.); (M.M.E.); (A.H.B.); (A.M.E.-M.); (A.H.)
- Pharmaceutical Chemistry Department, College of Pharmacy, The Islamic University, Najaf 54001, Iraq
| | - Mohammed Almaghrabi
- Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia; (A.K.B.A.); (M.A.); (M.A.)
| | - Aeshah A. Awaji
- Department of Biology, Faculty of Science, University College of Taymaa, University of Tabuk, Tabuk 71491, Saudi Arabia;
| | - Ali Hammad
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt (M.A.S.); (M.M.E.); (A.H.B.); (A.M.E.-M.); (A.H.)
| | - Marwa Alsulaimany
- Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia; (A.K.B.A.); (M.A.); (M.A.)
| | - Hany E. A. Ahmed
- Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt (M.A.S.); (M.M.E.); (A.H.B.); (A.M.E.-M.); (A.H.)
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Seong M, Park S, Kim ST, Goo Park S, Kim Y, Cha J, Yeop Kim E, Kim HJ, Ahn MJ. Increasing discrepancy of MR imaging and CSF study in patients with leptomeningeal seeding from lung adenocarcinoma after targeted therapy using a tyrosine kinase inhibitor. Medicine (Baltimore) 2023; 102:e35387. [PMID: 37800766 PMCID: PMC10552999 DOI: 10.1097/md.0000000000035387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 09/04/2023] [Indexed: 10/07/2023] Open
Abstract
PURPOSE To evaluate the correlation between contrast-enhanced (CE) MRI and cerebrospinal fluid (CSF) cytology for the evaluation of leptomeningeal metastasis (LM) on MRI after targeted therapy with tyrosine kinase inhibitors. METHODS We retrospectively reviewed the data of nonsmall cell lung cancer patients registered with NCT03257124 from May 2017 to December 2018, with progressive disease despite targeted therapy. Twenty-nine patients whose MRI scans exhibited LM at the time of registration were enrolled. During the targeted therapy with osimertinib, MRI scans, and subsequent CSF examinations were performed in every 2 months. In total, 113 MRI scans and CSF cytology data after treatment were collected. For each CE MRI scan, LM positivity was evaluated on 3D T1-weighted image (T1WI) and 2D FLAIR. The correlation between MRI and CSF cytology results and the diagnostic performance of MRI with CSF cytology as a reference standard were evaluated. RESULTS After treatment, MRI revealed positivity for LM in 81 and negativity in 32. CSF results were positive in 69 examinations and negative in 44. The diagnostic accuracy of CE 3D T1WI and 2D FLAIR was 0.52 and 0.46, respectively. After targeted therapy, discrepancy in the CSF and MRI results tended to increase over time. The proportions of concordant MRI and CSF cytology results after targeted therapy were 66%, 58%, 62%, and 47% at the first, second, third, and fourth follow-up, respectively. CONCLUSION The discrepancy of MRI in evaluation of LM and CSF cytology increases over time after targeted therapy with osimertinib. LM positivity on MRI could be a surrogate imaging marker in the pre- and immediate posttargeted-treatment with Osimertinib but not after sessions of osimertinib.
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Affiliation(s)
- Minjung Seong
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sehhoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Tae Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sung Goo Park
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yikyung Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jihoon Cha
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eung Yeop Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyung-Jin Kim
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myung-Ju Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Li S, Sun Y. Phytochemicals targeting epidermal growth factor receptor (EGFR) for the prevention and treatment of HNSCC: A review. Medicine (Baltimore) 2023; 102:e34439. [PMID: 37800790 PMCID: PMC10553117 DOI: 10.1097/md.0000000000034439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/30/2023] [Indexed: 10/07/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) develops from the mucosal epithelium of the oral cavity, pharynx, and larynx, and is the most common malignancy of the head and neck, the incidence of which continues to rise. The epidermal growth factor receptor is thought to play a key role in the pathogenesis of HNSCC. Inhibition of epidermal growth factor receptor has been identified as an effective target for the treatment of HNSCC. Many phytochemicals have emerged as potential new drugs for the treatment of HNSCC. A systematic search was conducted for research articles published in PubMed, and Medline on relevant aspects. This review provides an overview of the available literature and reports highlighting the in vitro effects of phytochemicals on epidermal growth factor in various HNSCC cell models and in vivo in animal models and emphasizes the importance of epidermal growth factor as a current therapeutic target for HNSCC. Based on our review, we conclude that phytochemicals targeting the epidermal growth factor receptor are potentially effective candidates for the development of new drugs for the treatment of HNSCC. It provides an idea for further development and application of herbal medicines for cancer treatment.
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Affiliation(s)
- Shaling Li
- The Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University, Longmatan District, Luzhou City, Sichuan Province, China
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Lee S, Kang E, Lee U, Cho S. Role of pelitinib in the regulation of migration and invasion of hepatocellular carcinoma cells via inhibition of Twist1. BMC Cancer 2023; 23:703. [PMID: 37495969 PMCID: PMC10373356 DOI: 10.1186/s12885-023-11217-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 07/24/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND Overexpression of Twist1, one of the epithelial-mesenchymal transition-transcription factors (EMT-TFs), is associated with hepatocellular carcinoma (HCC) metastasis. Pelitinib is known to be an irreversible epidermal growth factor receptor tyrosine kinase inhibitor that is used in clinical trials for colorectal and lung cancers, but the role of pelitinib in cancer metastasis has not been studied. This study aimed to investigate the anti-migration and anti-invasion activities of pelitinib in HCC cell lines. METHODS Using three HCC cell lines (Huh7, Hep3B, and SNU449 cells), the effects of pelitinib on cell cytotoxicity, invasion, and migration were determined by cell viability, wound healing, transwell invasion, and spheroid invasion assays. The activities of MMP-2 and -9 were examined through gelatin zymography. Through immunoblotting analyses, the expression levels of EMT-TFs (Snail1, Twist1, and ZEB1) and EMT-related signaling pathways such as mitogen-activated protein kinases (MAPKs) and Akt signaling pathways were measured. The activity and expression levels of target genes were analyzed by reporter assay, RT-PCR, quantitative RT-PCR, and immunoblotting analysis. Statistical analysis was performed using one-way ANOVA with Dunnett's Multiple comparison tests in Prism 3.0 to assess differences between experimental conditions. RESULTS In this study, pelitinib treatment significantly inhibited wound closure in various HCC cell lines, including Huh7, Hep3B, and SNU449. Additionally, pelitinib was found to inhibit multicellular cancer spheroid invasion and metalloprotease activities in Huh7 cells. Further investigation revealed that pelitinib treatment inhibited the migration and invasion of Huh7 cells by inducing Twist1 degradation through the inhibition of MAPK and Akt signaling pathways. We also confirmed that the inhibition of cell motility by Twist1 siRNA was similar to that observed in pelitinib-treated group. Furthermore, pelitinib treatment regulated the expression of target genes associated with EMT, as demonstrated by the upregulation of E-cadherin and downregulation of N-cadherin. CONCLUSION Based on our novel finding of pelitinib from the perspective of EMT, pelitinib has the ability to inhibit EMT activity of HCC cells via inhibition of Twist1, and this may be the potential mechanism of pelitinib on the suppression of migration and invasion of HCC cells. Therefore, pelitinib could be developed as a potential anti-cancer drug for HCC.
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Affiliation(s)
- Sewoong Lee
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Eunjeong Kang
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Unju Lee
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Sayeon Cho
- Laboratory of Molecular and Pharmacological Cell Biology, College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.
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Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther 2023; 8:198. [PMID: 37169756 PMCID: PMC10175505 DOI: 10.1038/s41392-023-01460-1] [Citation(s) in RCA: 408] [Impact Index Per Article: 204.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/20/2023] [Accepted: 04/20/2023] [Indexed: 05/13/2023] Open
Abstract
Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology, various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.
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Affiliation(s)
- Zhen-Ling Liu
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Huan-Huan Chen
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Li Zheng
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Ping Sun
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
| | - Lei Shi
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
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Wang Q, Zeng A, Zhu M, Song L. Dual inhibition of EGFR‑VEGF: An effective approach to the treatment of advanced non‑small cell lung cancer with EGFR mutation (Review). Int J Oncol 2023; 62:26. [PMID: 36601768 PMCID: PMC9851127 DOI: 10.3892/ijo.2023.5474] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 12/01/2022] [Indexed: 01/04/2023] Open
Abstract
On a global scale, the incidence and mortality rates of lung cancer are gradually increasing year by year. A number of bad habits and environmental factors are associated with lung cancer, including smoking, second‑hand smoke exposure, occupational exposure, respiratory diseases and genetics. At present, low‑dose spiral computed tomography is routinely the first choice in the diagnosis of lung cancer. However, pathological examination is still the gold standard for the diagnosis of lung cancer. Based on the classification and stage of the cancer, treatment options such as surgery, radiotherapy, chemotherapy, targeted therapy and immunotherapy are available. The activation of the EGFR pathway can promote the survival and proliferation of tumor cells, and the VEGF pathway can promote the formation of blood vessels, thereby promoting tumor growth. In non‑small cell lung cancer (NSCLC) with EGFR mutation, EGFR activation can promote tumor growth by promoting VEGF upregulation through a hypoxia‑independent mechanism. The upregulation of VEGF can make tumor cells resistant to EGFR inhibitors. In addition, the expression of the VEGF signal is also affected by other factors. Therefore, the use of a single EGFR inhibitor cannot completely inhibit the expression of the VEGF signal. In order to overcome this problem, the combination of VEGF inhibitors and EGFR inhibitors has become the method of choice. Dual inhibition can not only overcome the resistance of tumor cells to EGFR inhibitors, but also significantly increase the progression‑free survival time of patients with NSCLC. The present review discusses the associations between the EGFR and VEGF pathways, and the characteristics of dual inhibition of the EGFR‑VEGF pathway.
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Affiliation(s)
- Qian Wang
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan 610041, P.R. China
| | - Min Zhu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China,Correspondence to: Dr Linjiang Song or Dr Min Zhu, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu, Sichuan 611137, P.R. China, E-mail: , E-mail:
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, P.R. China,Correspondence to: Dr Linjiang Song or Dr Min Zhu, School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Chengdu, Sichuan 611137, P.R. China, E-mail: , E-mail:
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11
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Taha AM, Aboulwafa MM, Zedan H, Helmy OM. Ramucirumab combination with sorafenib enhances the inhibitory effect of sorafenib on HepG2 cancer cells. Sci Rep 2022; 12:17889. [PMID: 36284117 PMCID: PMC9596484 DOI: 10.1038/s41598-022-21582-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 09/29/2022] [Indexed: 01/20/2023] Open
Abstract
Sorafenib, an oral multiple kinase inhibitor, is the standardized treatment for hepatocellular carcinoma (HCC). One strategy to improve HCC therapy is to combine agents that target key signaling pathways. In this study we set out to investigate the effect of combining sorafenib with either bevacizumab (anti-VEGF), panitumumab (anti-EGFR) or ramucirumab (anti-VEGFR2) on HepG2 cancer cell line with the aim of improving efficacy and possibility of therapeutic dose reduction of sorafenib.: HepG2 cancer cell line was treated with sorafenib alone or in combination with either bevacizumab, panitumumab or ramucirumab. Cell proliferation; apoptosis and cell cycle distribution; gene expression of VEGFR2, EGFR, MMP-9 and CASPASE3; the protein levels of pVEGFR2 and pSTAT3 and the protein expression of CASPASE3, EGFR and VEGFR2 were determined. Combined treatments of sorafenib with ramucirumab or panitumumab resulted in a significant decrease in sorafenib IC50. Sorafenib combination with ramucirumab or bevacizumab resulted in a significant arrest in pre-G and G0/G1 cell cycle phases, significantly induced apoptosis and increased the relative expression of CASPASE3 and decreased the anti-proliferative and angiogenesis markers´ MMP-9 and pVEGFR2 or VEGFR2 in HepG2 cells. A significant decrease in the levels of pSTAT3 was only detected in case of sorafenib-ramucirumab combination. The combined treatment of sorafenib with panitumumab induced a significant arrest in pre-G and G2/M cell cycle phases and significantly decreased the relative expression of EGFR and MMP-9. Sorafenib-ramucirumab combination showed enhanced apoptosis, inhibited proliferation and angiogenesis in HepG2 cancer cells. Our findings suggest that ramucirumab can be a useful as an adjunct therapy for improvement of sorafenib efficacy in suppression of HCC.
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Affiliation(s)
| | - Mohammad Mabrouk Aboulwafa
- grid.7269.a0000 0004 0621 1570Department of Microbiology and Immunology, Faculty of Pharmacy, Ain Shams University, Al Khalifa Al Ma’moun St., Abbassia, Cairo, Egypt ,Present Address: Faculty of Pharmacy, King Salman International University, Ras-Sudr, South Sinai Egypt
| | - Hamdallah Zedan
- grid.7776.10000 0004 0639 9286Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-eini St., Cairo, Egypt
| | - Omneya Mohamed Helmy
- grid.7776.10000 0004 0639 9286Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Kasr El-eini St., Cairo, Egypt
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12
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Design and synthesis of some new 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines as multi tyrosine kinase inhibitors. Bioorg Chem 2022; 128:106099. [PMID: 35994884 DOI: 10.1016/j.bioorg.2022.106099] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/08/2022] [Accepted: 08/11/2022] [Indexed: 11/24/2022]
Abstract
The present study involves design and synthesis of five series of 6-bromo-2-(pyridin-3-yl)-4-substituted quinazolines 9a-l, 11a-e, 13a-c, 14a-f and 15a-e. Candidates 9a-l and 11a-e were evaluated for their EGFR and HER2 inhibitory activity compared to Lapatinib. Compounds 9b, 9d, 9f, 11b and 11c were further screened for their in vitro cytotoxicity against two human breast cancer cell lines: AU-565 and MDA-MB-231 in addition to normal breast cell line MCF10A. Compound 9d revealed a remarkable cytotoxic efficacy against AU-565 cell line (IC50 = 1.54 µM) relative to Lapatinib (IC50 = 0.48 µM), whereas compounds 9d and 11c showed a superior cytotoxicity towards MDA-MB-231 (IC50 = 2.67 and 1.75 µM, respectively) in comparison to Lapatinib (IC50 = 9.29 µM). Moreover, compounds 13a-c, 13a-c, 14a-f and 15a-e were tested for their VEGFR-2 inhibitory activity compared to Sorafenib. Compounds 13a, 14c and 14e exhibited remarkable inhibition (IC50 = 79.80, 50.22 and 78.02 nM, respectively) relative to Sorafenib (IC50 = 51.87 nM). In vitro cytotoxicity of these compounds against HepG2, HCT-116 and normal cell (WISH) revealed a superior cytotoxicity against HepG2, HCT-116 especially 13a (IC50 = 17.51 and 5.56 µM, respectively) and 14c (IC50 = 10.40 and 3.37 µM, respectively) compared to Sorafenib (IC50 = 19.33 and 6.82 µM, respectively). Compounds 9d, 11c and 14c were subjected to cell cycle analysis and apoptotic assay. Molecular docking and ADME prediction studies were fulfilled to illustrate the interaction of the potent derivatives with the hot spots of the active site of EGFR, HER2 and VEGFR-2 along with prediction of their pharmacokinetic and physicochemical properties.
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Mohammadzadeh V, Rahiman N, Hosseinikhah SM, Barani M, Rahdar A, Jaafari MR, Sargazi S, Zirak MR, Pandey S, Bhattacharjee R, Gupta AK, Thakur VK, Sibuh BZ, Gupta PK. Novel EPR-enhanced strategies for targeted drug delivery in pancreatic cancer: An update. J Drug Deliv Sci Technol 2022. [DOI: 10.1016/j.jddst.2022.103459] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Biomarker LEPRE1 induces pelitinib-specific drug responsiveness by regulating ABCG2 expression and tumor transition states in human leukemia and lung cancer. Sci Rep 2022; 12:2928. [PMID: 35190588 PMCID: PMC8861100 DOI: 10.1038/s41598-022-06621-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 01/28/2022] [Indexed: 12/31/2022] Open
Abstract
Biomarkers for treatment sensitivity or drug resistance used in precision medicine include prognostic and predictive molecules, critical factors in selecting appropriate treatment protocols and improving survival rates. However, identification of accurate biomarkers remain challenging due to the high risk of false-positive findings and lack of functional validation results for each biomarker. Here, we discovered a mechanical correlation between leucine proline-enriched proteoglycan 1 (LEPRE1) and pelitinib drug sensitivity using in silico statistical methods and confirmed the correlation in acute myeloid leukemia (AML) and A549 lung cancer cells. We determined that high LEPRE1 levels induce protein kinase B activation, overexpression of ATP-binding cassette superfamily G member 2 (ABCG2) and E-cadherin, and cell colonization, resulting in a cancer stem cell-like phenotype. Sensitivity to pelitinib increases in LEPRE1-overexpressing cells due to the reversing effect of ABCG2 upregulation. LEPRE1 silencing induces pelitinib resistance and promotes epithelial-to-mesenchymal transition through actin rearrangement via a series of Src/ERK/cofilin cascades. The in silico results identified a mechanistic relationship between LEPRE1 and pelitinib drug sensitivity, confirmed in two cancer types. This study demonstrates the potential of LEPRE1 as a biomarker in cancer through in-silico prediction and in vitro experiments supporting the clinical development of personalized medicine strategies based on bioinformatics findings.
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15
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The Chemokine-Based Peptide, CXCL9(74-103), Inhibits Angiogenesis by Blocking Heparan Sulfate Proteoglycan-Mediated Signaling of Multiple Endothelial Growth Factors. Cancers (Basel) 2021; 13:cancers13205090. [PMID: 34680238 PMCID: PMC8534003 DOI: 10.3390/cancers13205090] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Major angiogenic growth factors activate downstream signaling cascades by interacting with both receptor tyrosine kinases (RTKs) and cell surface proteoglycans, such as heparan sulfate proteoglycans (HSPGs). As current anti-angiogenesis regimens in cancer are often faced with resistance, alternative therapeutic strategies are highly needed. The aim of our study was to investigate the impact on angiogenic signaling when we interfered with growth factor-HSPG interactions using a CXCL9 chemokine-derived peptide with high affinity for HS. Abstract Growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF) and epidermal growth factor (EGF) are important angiogenesis-mediating factors. They exert their effects not only through their respective receptor tyrosine kinases (RTKs), but they also require molecular pairing with heparan sulfate proteoglycans (HSPGs). Angiogenic growth factors and their signaling pathways are commonly targeted in current anti-angiogenic cancer therapies but have unfortunately insufficient impact on patient survival. Considering their obvious role in pathological angiogenesis, HS-targeting drugs have become an appealing new strategy. Therefore, we aimed to reduce angiogenesis through interference with growth factor-HS binding and downstream signaling using a CXCL9-derived peptide with a high affinity for glycosaminoglycans (GAGs), CXCL9(74-103). We showed that CXCL9(74-103) reduced EGF-, VEGF165- and FGF-2-mediated angiogenic processes in vitro, such as endothelial cell proliferation, chemotaxis, adhesion and sprouting, without exerting cell toxicity. CXCL9(74-103) interfered with growth factor signaling in diverse ways, e.g., by diminishing VEGF165 binding to HS and by direct association with FGF-2. The dependency of CXCL9(74-103) on HS for binding to HMVECs and for exerting its anti-angiogenic activity was also demonstrated. In vivo, CXCL9(74-103) attenuated neovascularization in the Matrigel plug assay, the corneal cauterization assay and in MDA-MB-231 breast cancer xenografts. Additionally, CXCL9(74-103) reduced vascular leakage in the retina of diabetic rats. In contrast, CXCL9(86-103), a peptide with low GAG affinity, showed no overall anti-angiogenic activity. Altogether, our results indicate that CXCL9(74-103) reduces angiogenesis by interfering with multiple HS-dependent growth factor signaling pathways.
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Rickard BP, Conrad C, Sorrin AJ, Ruhi MK, Reader JC, Huang SA, Franco W, Scarcelli G, Polacheck WJ, Roque DM, del Carmen MG, Huang HC, Demirci U, Rizvi I. Malignant Ascites in Ovarian Cancer: Cellular, Acellular, and Biophysical Determinants of Molecular Characteristics and Therapy Response. Cancers (Basel) 2021; 13:4318. [PMID: 34503128 PMCID: PMC8430600 DOI: 10.3390/cancers13174318] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/17/2021] [Accepted: 08/22/2021] [Indexed: 12/27/2022] Open
Abstract
Ascites refers to the abnormal accumulation of fluid in the peritoneum resulting from an underlying pathology, such as metastatic cancer. Among all cancers, advanced-stage epithelial ovarian cancer is most frequently associated with the production of malignant ascites and is the leading cause of death from gynecologic malignancies. Despite decades of evidence showing that the accumulation of peritoneal fluid portends the poorest outcomes for cancer patients, the role of malignant ascites in promoting metastasis and therapy resistance remains poorly understood. This review summarizes the current understanding of malignant ascites, with a focus on ovarian cancer. The first section provides an overview of heterogeneity in ovarian cancer and the pathophysiology of malignant ascites. Next, analytical methods used to characterize the cellular and acellular components of malignant ascites, as well the role of these components in modulating cell biology, are discussed. The review then provides a perspective on the pressures and forces that tumors are subjected to in the presence of malignant ascites and the impact of physical stress on therapy resistance. Treatment options for malignant ascites, including surgical, pharmacological and photochemical interventions are then discussed to highlight challenges and opportunities at the interface of drug discovery, device development and physical sciences in oncology.
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Affiliation(s)
- Brittany P. Rickard
- Curriculum in Toxicology & Environmental Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
| | - Christina Conrad
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (C.C.); (A.J.S.); (G.S.); (H.-C.H.)
| | - Aaron J. Sorrin
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (C.C.); (A.J.S.); (G.S.); (H.-C.H.)
| | - Mustafa Kemal Ruhi
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
| | - Jocelyn C. Reader
- Department of Obstetrics, Gynecology and Reproductive Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (J.C.R.); (D.M.R.)
- Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Stephanie A. Huang
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
| | - Walfre Franco
- Department of Biomedical Engineering, University of Massachusetts Lowell, Lowell, MA 01854, USA;
| | - Giuliano Scarcelli
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (C.C.); (A.J.S.); (G.S.); (H.-C.H.)
| | - William J. Polacheck
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
- Department of Cell Biology and Physiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Dana M. Roque
- Department of Obstetrics, Gynecology and Reproductive Medicine, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; (J.C.R.); (D.M.R.)
- Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Marcela G. del Carmen
- Division of Gynecologic Oncology, Vincent Obstetrics and Gynecology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA;
| | - Huang-Chiao Huang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; (C.C.); (A.J.S.); (G.S.); (H.-C.H.)
- Marlene and Stewart Greenebaum Cancer Center, School of Medicine, University of Maryland, Baltimore, MD 21201, USA
| | - Utkan Demirci
- Bio-Acoustic MEMS in Medicine (BAMM) Laboratory, Canary Center at Stanford for Cancer Early Detection, Department of Radiology, School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
| | - Imran Rizvi
- Curriculum in Toxicology & Environmental Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC, and North Carolina State University, Raleigh, NC 27599, USA; (M.K.R.); (S.A.H.); (W.J.P.)
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Shaikh M, Shinde Y, Pawara R, Noolvi M, Surana S, Ahmad I, Patel H. Emerging Approaches to Overcome Acquired Drug Resistance Obstacles to Osimertinib in Non-Small-Cell Lung Cancer. J Med Chem 2021; 65:1008-1046. [PMID: 34323489 DOI: 10.1021/acs.jmedchem.1c00876] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The pyrimidine core-containing compound Osimertinib is the only epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) from the third generation that has been approved by the U.S. Food and Drug Administration to target threonine 790 methionine (T790M) resistance while sparing the wild-type epidermal growth factor receptor (WT EGFR). It is nearly 200-fold more selective toward the mutant EGFR as compared to the WT EGFR. A tertiary cystein 797 to serine 797 (C797S) mutation in the EGFR kinase domain has hampered Osimertinib treatment in patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC). This C797S mutation is presumed to induce a tertiary-acquired resistance to all current reversible and irreversible EGFR TKIs. This review summarizes the molecular mechanisms of resistance to Osimertinib as well as different strategies for overcoming the EGFR-dependent and EGFR-independent mechanisms of resistance, new challenges, and a future direction.
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Affiliation(s)
- Matin Shaikh
- H. R. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India 425405
| | - Yashodeep Shinde
- R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India 425405
| | - Rahul Pawara
- R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India 425405
| | - Malleshappa Noolvi
- Shree Dhanvantari College of Pharmacy, Kim, Surat, Gujarat, India 394111
| | - Sanjay Surana
- R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India 425405
| | - Iqrar Ahmad
- R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India 425405
| | - Harun Patel
- R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Maharashtra, India 425405
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Wu Y, Ni H, Yang D, Niu Y, Chen K, Xu J, Wang F, Tang S, Shi Y, Zhang H, Hu J, Xia D, Wu Y. Driver and novel genes correlated with metastasis of non-small cell lung cancer: A comprehensive analysis. Pathol Res Pract 2021; 224:153551. [PMID: 34298439 DOI: 10.1016/j.prp.2021.153551] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/15/2022]
Abstract
Although mutations of genes are crucial events in tumorigenesis and development, the association between gene mutations and lung cancer metastasis is still largely unknown. The goal of this study is to identify driver and novel genes associated with non-small cell lung cancer (NSCLC) metastasis. Candidate genes were identified using a novel comprehensive analysis, which was based on bioinformatics technology and meta-analysis. Firstly, EGFR, KRAS, ALK, TP53, BRAF and PIK3CA were identified as candidate driver genes. Further meta-analysis identified that EGFR (Pooled OR 1.33, 95% CI 1.19, 1.50; P < .001) and ALK (Pooled OR 1.52, 95% CI 1.22, 1.89; P < .001) mutations were associated with distant metastasis of NSCLC. Besides, ALK (Pooled OR 2.40, 95% CI 1.71, 3.38; P < .001) mutation was associated with lymph node metastasis of NSCLC. In addition, thirteen novel gene mutations were identified to be correlated with NSCLC metastasis, including SMARCA1, GGCX, KIF24, LRRK1, LILRA4, OR2T10, EDNRB, NR1H4, ARID4A, PRKCI, PABPC5, ACAN and TLN1. Furthermore, elevated mRNA expression level of SMARCA1 and EDNRB was associated with poor overall survival in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively. Additionally, pathway and protein-protein interactions network analyses found the two genes were correlated with epithelial-mesenchymal transition process. In conclusion, mutations of EGFR and ALK were significantly correlated with NSCLC metastasis. In addition, thirteen novel genes were identified to be associated with NSCLC metastasis, especially SMARCA1 in LUAD and EDNRB in LUSC.
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Affiliation(s)
- Yongfeng Wu
- Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China; Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Heng Ni
- Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China; Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Dexin Yang
- Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Yuequn Niu
- Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Kelie Chen
- Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Jinming Xu
- Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Fang Wang
- Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Song Tang
- Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Yu Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Honghe Zhang
- Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China
| | - Jian Hu
- Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
| | - Dajing Xia
- Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China.
| | - Yihua Wu
- Department of Toxicology of School of Public Health, and Department of Gynecologic Oncology of Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China; Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences, Hangzhou 310058, China.
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19
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Mamatha SV, Belagali SL, Bhat M, Kumbar VM. Design and Synthesis of Novel Coumarin Conjugated Acetamides as Promising Anticancer Agents: An In Silico and In Vitro Approach. Anticancer Agents Med Chem 2021; 21:1431-1440. [PMID: 32664844 DOI: 10.2174/1871520620666200714140820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 04/23/2020] [Accepted: 05/10/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Coumarin and benzophenone possess a vast sphere of biological activities, whereas thiazoles display various pharmacological properties. Hence, present study focused on the incorporation of coumarin and thiazole core to the benzophenone skeleton to enhance the bioactivity, anticipating their interesting biological properties. OBJECTIVE The objective of the current work is the synthesis and biological evaluation of a novel series of coumarin fused thiazole derivatives. METHODS A novel series of coumarin conjugated thiazolyl acetamide hybrid derivatives were synthesized by a multistep reaction sequence and were characterized by the FT-IR, LCMS, and NMR spectral techniques. The newly synthesized compounds were screened for anti-cancer activity by in silico and in vitro methods. The cytotoxicity of the synthesized unique compounds was executed for two different cancer cell lines, MCF-7 (Breast cancer) and KB (Oral cancer), in comparison with standard paclitaxel by MTT assay. RESULTS The compound 7f is a potent motif with an acceptable range of IC50 values, for anti-cancer activity, i.e., 63.54μg/ml and 55.67μg/ml, against the MCF-7 and KB cell lines, respectively. Molecule docking model revealed that this compound formed three conventional hydrogen bonds with the active sites of the amino acids, MET 769, ARG 817, and LYS 721. CONCLUSION Compound 7f with two methyl groups on the phenoxy ring and one 4-position methoxy group on the benzoyl ring, showed a significant cytotoxic effect. An advantageous level of low toxicity against normal cell line (L292) by MTT assay was determined.
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Affiliation(s)
- S V Mamatha
- Department of Studies in Environmental Science, Environmental Chemistry Section, University of Mysore, Manasagangothri, Mysuru- 570 006, Karnataka, India
| | - Shiddappa L Belagali
- Department of Studies in Environmental Science, Environmental Chemistry Section, University of Mysore, Manasagangothri, Mysuru- 570 006, Karnataka, India
| | - Mahesh Bhat
- PG Department of Chemistry, JSS College for Women, Mysore- 580 009, Karnataka, India
| | - Vijay M Kumbar
- Central Research Laboratory, Maratha Mandal's Nathajirao G. Halgekar Institute of Dental Sciences and Research Centre, Belagavi-590010, Karnataka, India
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20
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Dorrell MI, Kast-Woelbern HR, Botts RT, Bravo SA, Tremblay JR, Giles S, Wada JF, Alexander M, Garcia E, Villegas G, Booth CB, Purington KJ, Everett HM, Siles EN, Wheelock M, Silva JA, Fortin BM, Lowey CA, Hale AL, Kurz TL, Rusing JC, Goral DM, Thompson P, Johnson AM, Elson DJ, Tadros R, Gillette CE, Coopwood C, Rausch AL, Snowbarger JM. A novel method of screening combinations of angiostatics identifies bevacizumab and temsirolimus as synergistic inhibitors of glioma-induced angiogenesis. PLoS One 2021; 16:e0252233. [PMID: 34077449 PMCID: PMC8172048 DOI: 10.1371/journal.pone.0252233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/11/2021] [Indexed: 12/15/2022] Open
Abstract
Tumor angiogenesis is critical for the growth and progression of cancer. As such, angiostasis is a treatment modality for cancer with potential utility for multiple types of cancer and fewer side effects. However, clinical success of angiostatic monotherapies has been moderate, at best, causing angiostatic treatments to lose their early luster. Previous studies demonstrated compensatory mechanisms that drive tumor vascularization despite the use of angiostatic monotherapies, as well as the potential for combination angiostatic therapies to overcome these compensatory mechanisms. We screened clinically approved angiostatics to identify specific combinations that confer potent inhibition of tumor-induced angiogenesis. We used a novel modification of the ex ovo chick chorioallantoic membrane (CAM) model that combined confocal and automated analyses to quantify tumor angiogenesis induced by glioblastoma tumor onplants. This model is advantageous due to its low cost and moderate throughput capabilities, while maintaining complex in vivo cellular interactions that are difficult to replicate in vitro. After screening multiple combinations, we determined that glioblastoma-induced angiogenesis was significantly reduced using a combination of bevacizumab (Avastin®) and temsirolimus (Torisel®) at doses below those where neither monotherapy demonstrated activity. These preliminary results were verified extensively, with this combination therapy effective even at concentrations further reduced 10-fold with a CI value of 2.42E-5, demonstrating high levels of synergy. Thus, combining bevacizumab and temsirolimus has great potential to increase the efficacy of angiostatic therapy and lower required dosing for improved clinical success and reduced side effects in glioblastoma patients.
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Affiliation(s)
- Michael I. Dorrell
- Department of Biology, Point Loma Nazarene University, San Diego, CA, United States of America
- * E-mail:
| | - Heidi R. Kast-Woelbern
- Department of Biology, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Ryan T. Botts
- Department of Mathematical, Information, and Computer Sciences, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Stephen A. Bravo
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Jacob R. Tremblay
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Sarah Giles
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Jessica F. Wada
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - MaryAnn Alexander
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Eric Garcia
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Gabriel Villegas
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Caylor B. Booth
- Department of Mathematical, Information, and Computer Sciences, Dr. Ryan Bott’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Kaitlyn J. Purington
- Department of Mathematical, Information, and Computer Sciences, Dr. Ryan Bott’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Haylie M. Everett
- Department of Mathematical, Information, and Computer Sciences, Dr. Ryan Bott’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Erik N. Siles
- Department of Mathematical, Information, and Computer Sciences, Dr. Ryan Bott’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Michael Wheelock
- Department of Mathematical, Information, and Computer Sciences, Dr. Ryan Bott’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Jordan A. Silva
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Bridget M. Fortin
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Connor A. Lowey
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Allison L. Hale
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Troy L. Kurz
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Jack C. Rusing
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Dawn M. Goral
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Paul Thompson
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Alec M. Johnson
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Daniel J. Elson
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Roujih Tadros
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Charisa E. Gillette
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Carley Coopwood
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Amy L. Rausch
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
| | - Jeffrey M. Snowbarger
- Department of Biology, Dr. Michael Dorrell’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
- Department of Biology, Dr. Heidi R. Kast-Woelbern’s Lab, Point Loma Nazarene University, San Diego, CA, United States of America
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21
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Chung C. Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation. J Oncol Pharm Pract 2021; 28:850-869. [PMID: 33832365 DOI: 10.1177/10781552211005525] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [NTRK] fusion genes, and human epidermal growth factor receptor type II [HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.
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Affiliation(s)
- Clement Chung
- 23530Houston Methodist West Hospital, Houston, TX, USA
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22
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Hadifar S, Mostafaei S, Behrouzi A, Fateh A, Riahi P, Siadat SD, Vaziri F. Strain-specific behavior of Mycobacterium tuberculosis in A549 lung cancer cell line. BMC Bioinformatics 2021; 22:154. [PMID: 33765916 PMCID: PMC7992940 DOI: 10.1186/s12859-021-04100-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Accepted: 03/23/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND A growing body of evidence has shown the association between tuberculosis (TB) infection and lung cancer. However, the possible effect of strain-specific behavior of Mycobacterium tuberculosis (M.tb) population, the etiological agent of TB infection in this association has been neglected. In this context, this study was conducted to investigate this association with consideration of the genetic background of strains in the M.tb population. RESULTS We employed the elastic net penalized logistic regression model, as a statistical-learning algorithm for gene selection, to evaluate this association in 129 genes involved in TLRs and NF-κB signaling pathways in response to two different M.tb sub-lineage strains (L3-CAS1and L 4.5). Of the 129 genes, 21 were found to be associated with the two studied M.tb sub-lineages. In addition, MAPK8IP3 gene was identified as a novel gene, which has not been reported in previous lung cancer studies and may have the potential to be recognized as a novel biomarker in lung cancer investigation. CONCLUSIONS This preliminary study provides new insights into the mechanistic association between TB infection and lung cancer. Further mechanistic investigations of this association with a large number of M.tb strains, encompassing the other main M.tb lineages and using the whole transcriptome of the host cell are inevitable.
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Affiliation(s)
- Shima Hadifar
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Shayan Mostafaei
- Department of Biostatistics, School of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Epidemiology and Biostatistics Unit, Rheumatology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Ava Behrouzi
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Abolfazl Fateh
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Parisa Riahi
- Department of Biostatistics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Davar Siadat
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran
| | - Farzam Vaziri
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran, Iran.
- Microbiology Research Center (MRC), Pasteur Institute of Iran, Tehran, Iran.
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23
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The Multifaceted Roles of EGFL7 in Cancer and Drug Resistance. Cancers (Basel) 2021; 13:cancers13051014. [PMID: 33804387 PMCID: PMC7957479 DOI: 10.3390/cancers13051014] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 02/20/2021] [Accepted: 02/22/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Cancer growth and metastasis require interactions with the extracellular matrix (ECM), which is home to many biomolecules that support the formation of new vessels and cancer growth. One of these biomolecules is epidermal growth factor-like protein-7 (EGFL7). EGFL7 alters cellular adhesion to the ECM and migratory behavior of tumor and immune cells contributing to tumor metastasis. EGFL7 is engaged in the formation of new vessels and changes in ECM stiffness. One of its binding partners on the endothelial and cancer cell surface is beta 3 integrin. Beta 3 integrin pathways are under intense investigation in search of new therapies to kill cancer cells. All these properties enable EGFL7 to contribute to drug resistance. In this review, we give insight into recent studies on EGFL7 and its engagement with beta3 integrin, a marker predicting cancer stem cells and drug resistance. Abstract Invasion of cancer cells into surrounding tissue and the vasculature is an important step for tumor progression and the establishment of distant metastasis. The extracellular matrix (ECM) is home to many biomolecules that support new vessel formation and cancer growth. Endothelial cells release growth factors such as epidermal growth factor-like protein-7 (EGFL7), which contributes to the formation of the tumor vasculature. The signaling axis formed by EGFL7 and one of its receptors, beta 3 integrin, has emerged as a key mediator in the regulation of tumor metastasis and drug resistance. Here we summarize recent studies on the role of the ECM-linked angiocrine factor EGFL7 in primary tumor growth, neoangiogenesis, tumor metastasis by enhancing epithelial-mesenchymal transition, alterations in ECM rigidity, and drug resistance. We discuss its role in cellular adhesion and migration, vascular leakiness, and the anti-cancer response and provide background on its transcriptional regulation. Finally, we discuss its potential as a drug target as an anti-cancer strategy.
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24
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Huang D, Sun L, Huang L, Chen Y. Nanodrug Delivery Systems Modulate Tumor Vessels to Increase the Enhanced Permeability and Retention Effect. J Pers Med 2021; 11:124. [PMID: 33672813 PMCID: PMC7917988 DOI: 10.3390/jpm11020124] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/07/2021] [Accepted: 02/08/2021] [Indexed: 12/24/2022] Open
Abstract
The use of nanomedicine for antitumor therapy has been extensively investigated for a long time. Enhanced permeability and retention (EPR) effect-mediated drug delivery is currently regarded as an effective way to bring drugs to tumors, especially macromolecular drugs and drug-loaded pharmaceutical nanocarriers. However, a disordered vessel network, and occluded or embolized tumor blood vessels seriously limit the EPR effect. To augment the EPR effect and improve curative effects, in this review, we focused on the perspective of tumor blood vessels, and analyzed the relationship among abnormal angiogenesis, abnormal vascular structure, irregular blood flow, extensive permeability of tumor vessels, and the EPR effect. In this commentary, nanoparticles including liposomes, micelles, and polymers extravasate through the tumor vasculature, which are based on modulating tumor vessels, to increase the EPR effect, thereby increasing their therapeutic effect.
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Affiliation(s)
- Dong Huang
- Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China; (D.H.); (L.S.)
- Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Lingna Sun
- Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China; (D.H.); (L.S.)
- Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
| | - Leaf Huang
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA;
| | - Yanzuo Chen
- Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science and Technology, Shanghai 200237, China; (D.H.); (L.S.)
- Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China
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25
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Wang Q, Gavin W, Masiello N, Tran KB, Laible G, Shepherd PR. Cetuximab produced from a goat mammary gland expression system is equally efficacious as innovator cetuximab in animal cancer models. BIOTECHNOLOGY REPORTS (AMSTERDAM, NETHERLANDS) 2020; 28:e00533. [PMID: 33024714 PMCID: PMC7528048 DOI: 10.1016/j.btre.2020.e00533] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/10/2020] [Accepted: 09/21/2020] [Indexed: 11/24/2022]
Abstract
There is increasing demand for improved production and purification systems for biosimilar or biobetter humanised monoclonal antibodies and animal production systems offer one such possibile option. Cetuximab, also known as 'Erbitux', is a humanised monoclonal antibody widely used in cancer therapy. We have previously reported on a genetically engineered goat system to produce cetuximab (gCetuximab) in milk. Herein we report that gCetuximab has similar bioactivity and pharamacokinetic properties compared with the commercial product produced in mammalian cell culture. In particular both forms have very similar efficacy in a HT29 colorectal cancer xenograft model alone or when conjugated to the toxin MMAE. This also demonstrates that the gCetuximab will be a viable vehicle for antibody drug conjugate based therapies. Taken together, this shows that the goat milk monoclonal antibody production system is an effective way of producing a biosimilar form of cetuximab.
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Affiliation(s)
- Qian Wang
- School of Medical Sciences, University of Auckland, Auckland, 1023, New Zealand
| | | | | | - Khanh B. Tran
- School of Medical Sciences, University of Auckland, Auckland, 1023, New Zealand
| | - Götz Laible
- School of Medical Sciences, University of Auckland, Auckland, 1023, New Zealand
- AgResearch, Ruakura Research Centre, Hamilton, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Peter R. Shepherd
- School of Medical Sciences, University of Auckland, Auckland, 1023, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
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26
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uPAR-expressing melanoma exosomes promote angiogenesis by VE-Cadherin, EGFR and uPAR overexpression and rise of ERK1,2 signaling in endothelial cells. Cell Mol Life Sci 2020; 78:3057-3072. [PMID: 33237352 PMCID: PMC8004497 DOI: 10.1007/s00018-020-03707-4] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 11/02/2020] [Accepted: 11/06/2020] [Indexed: 12/19/2022]
Abstract
Exosomes (Exos) have been reported to promote pre-metastatic niche formation, proliferation, angiogenesis and metastasis. We have investigated the role of uPAR in melanoma cell lines-derived Exos and their pro-angiogenic effects on human microvascular endothelial cells (HMVECs) and endothelial colony-forming cells (ECFCs). Melanoma Exos were isolated from conditioned media of A375 and M6 cells by differential centrifugation and filtration. Tunable Resistive Pulse Sensing (TRPS) and Nanoparticle tracking analysis were performed to analyze dimension and concentration of Exos. The CRISPR–Cas 9 technology was exploited to obtain a robust uPAR knockout. uPAR is expressed in melanoma Exos that are internalized by HMVECs and ECFCs, enhancing VE-Cadherin, EGFR and uPAR expression in endothelial cells that undergo a complete angiogenic program, including proliferation, migration and tube formation. uPAR loss reduced the pro-angiogenic effects of melanoma Exos in vitro and in vivo by inhibition of VE-Cadherin, EGFR and uPAR expression and of ERK1,2 signaling in endothelial cells. A similar effect was obtained with a peptide that inhibits uPAR–EGFR interaction and with the EGFR inhibitor Gefitinib, which also inhibited melanoma Exos-dependent EGFR phosphorylation. This study suggests that uPAR is required for the pro-angiogenic activity of melanoma Exos. We propose the identification of uPAR-expressing Exos as a potentially useful biomarker for assessing pro-angiogenic propensity and eventually monitoring the response to treatment in metastatic melanoma patients.
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27
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Fodor K, Sipos É, Dobos N, Nagy J, Steiber Z, Méhes G, Dull K, Székvölgyi L, Schally AV, Halmos G. Correlation between the Expression of Angiogenic Factors and Stem Cell Markers in Human Uveal Melanoma. Life (Basel) 2020; 10:life10120310. [PMID: 33255843 PMCID: PMC7760175 DOI: 10.3390/life10120310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 11/18/2020] [Indexed: 12/17/2022] Open
Abstract
Uveal melanoma (UM) is the most common malignant tumor of the eye with extremely high metastatic potential. UM tumor cells can disseminate only hematogenously, thus, angiogenic signals have a particular role in the prognosis of the disease. Although the presence of cancer stem cells (CSCs) in densely vascularized UMs has been reported previously, their role in the process of hematogenous spread of UM has not been studied. In this study, we investigated the regulation of angiogenesis in UM in correlation with the presence of CSCs. Seventy UM samples were collected to analyze the expression of CSC markers and angiogenic factors. The expression of CSC markers was studied by RT-PCR, Western blotting techniques and IHC-TMA technique. RT-PCR showed high expression of CSC markers, particularly nestin, FZD6 and SOX10 and somewhat lower expression of NGFR. The protein expression of FZD6, HIF-1α and VEGFA was further evaluated in 52 UM samples by the IHC-TMA technique. We report here for the first time a significant correlation between FZD6 and VEGFA expression in UM samples. The observed correlation between FZD6 and VEGFA suggests the presence of CSCs in UM that are associated with the vascularization process.
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Affiliation(s)
- Klára Fodor
- Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (K.F.); (É.S.); (N.D.)
| | - Éva Sipos
- Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (K.F.); (É.S.); (N.D.)
| | - Nikoletta Dobos
- Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (K.F.); (É.S.); (N.D.)
| | - János Nagy
- Clinical Center, Department of Oncology, University of Debrecen, 4032 Debrecen, Hungary;
| | - Zita Steiber
- Clinical Center, Department of Ophthalmology, University of Debrecen, 4032 Debrecen, Hungary;
| | - Gábor Méhes
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (G.M.); (K.D.)
| | - Kata Dull
- Department of Pathology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (G.M.); (K.D.)
| | - Lóránt Székvölgyi
- MTA-DE Momentum, Genome Architecture and Recombination Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Andrew V. Schally
- Veterans Affairs Medical Center, Endocrine, Polypeptide and Cancer Institute, Miami, FL 33101, USA;
- Sylvester Comprehensive Cancer Center, Department of Medicine, Department of Pathology, Divisions of Hematology Oncology and Endocrinology, Miller School of Medicine, University of Miami, Miami, FL 33101, USA
| | - Gábor Halmos
- Department of Biopharmacy, Faculty of Pharmacy, University of Debrecen, 4032 Debrecen, Hungary; (K.F.); (É.S.); (N.D.)
- Veterans Affairs Medical Center, Endocrine, Polypeptide and Cancer Institute, Miami, FL 33101, USA;
- Correspondence: ; Tel.: +36-52-255-292
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28
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Tian W, Cao C, Shu L, Wu F. Anti-Angiogenic Therapy in the Treatment of Non-Small Cell Lung Cancer. Onco Targets Ther 2020; 13:12113-12129. [PMID: 33262610 PMCID: PMC7699985 DOI: 10.2147/ott.s276150] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 10/14/2020] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis plays an essential role in the development of most solid tumors by delivering nutrients and oxygen to the tumor. Therefore, anti-angiogenic therapy, particularly anti-VEGF and anti-VEGF receptor (VEGFR) therapy, has been a popular strategy to treat cancer. However, anti-angiogenic therapy does not significantly improve patients' outcomes when used alone because the cutdown of the vessels transforms tumor cells to a hypoxia-tolerant phenotype. While combining anti-angiogenic therapy with other therapies, including chemotherapy, radiotherapy, immunotherapy, and anti-epidermal growth factor receptor (EGFR) therapy, has a promising efficacy due to the vessel normalization effect induced by anti-angiogenic agents. Here, we review the characteristics of tumor angiogenesis, the mechanisms, clinical applications, and prospects of combining anti-angiogenic therapy with other therapies in the treatment of non-small cell lung cancer.
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Affiliation(s)
- Wentao Tian
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People's Republic of China.,Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China
| | - Chenghui Cao
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People's Republic of China.,Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China
| | - Long Shu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People's Republic of China
| | - Fang Wu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People's Republic of China
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29
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Xu C, Zhou W, Dong G, Qiao H, Peng J, Jia P, Li Y, Liu H, Sun K, Zhao W. Novel [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing hydrazone fragment as potent and selective anticancer agents. Bioorg Chem 2020; 105:104424. [PMID: 33161253 DOI: 10.1016/j.bioorg.2020.104424] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/18/2020] [Accepted: 10/20/2020] [Indexed: 01/22/2023]
Abstract
In this paper, based on molecular hybridization, a series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives containing hydrazine was synthesized and their antiproliferative activities against 5 cancer cell lines (MGC-803, PC3, PC9, EC9706 and SMMC-7721) were evaluated. We found that most of them exhibited obvious growth inhibition effects on these tested cancer cells, especially compound 34 on PC3 cells (IC50 = 26.25 ± 0.28 nM). Meanwhile, compound 34 displayed best selectivity on PC3, compared with the other cancer cell lines, as well as excellent selectivity towards normal cell lines (Het-1A, L02 and GES-1). Further investigations demonstrated that 34 could significantly inhibit PC3 cells' colony formation, increase cellular ROS content, suppress EGFR expression and induce apoptosis. Our findings indicate that 34 may serve as a novel lead compound for the discovery of more triazolopyrimidine derivatives with improved anticancer potency and selectivity.
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Affiliation(s)
- Chenhao Xu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Wenjuan Zhou
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Department of Pathology, Oslo University Hospital, Faculty of Medicine, University of Oslo, Oslo 0379, Norway
| | - Guanjun Dong
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Hui Qiao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Jiadi Peng
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Pengfei Jia
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Yuhao Li
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Hongmin Liu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China
| | - Kai Sun
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
| | - Wen Zhao
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Key Laboratory of Advanced Pharmaceutical Technology, Ministry of Education of China, Zhengzhou University School of Pharmaceutical Sciences and Institute of Drug Discovery & Development, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
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Izawa N, Shitara K, Yonesaka K, Yamanaka T, Yoshino T, Sunakawa Y, Masuishi T, Denda T, Yamazaki K, Moriwaki T, Okuda H, Kondoh C, Nishina T, Makiyama A, Baba H, Yamaguchi H, Nakamura M, Hyodo I, Muro K, Nakajima TE. Early Tumor Shrinkage and Depth of Response in the Second-Line Treatment for KRAS exon2 Wild-Type Metastatic Colorectal Cancer: An Exploratory Analysis of the Randomized Phase 2 Trial Comparing Panitumumab and Bevacizumab in Combination with FOLFIRI (WJOG6210G). Target Oncol 2020; 15:623-633. [PMID: 32960408 DOI: 10.1007/s11523-020-00750-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Predictive markers for the clinical outcomes of second-line treatment in patients with metastatic colorectal cancer (mCRC) remain unclear. OBJECTIVE This retrospective biomarker study was conducted to explore predictive markers for patients with KRAS exon 2 wild-type mCRC who were treated with FOLFIRI plus panitumumab (Pani) or bevacizumab (Bev) in the WJOG6210G trial. PATIENTS AND METHODS The associations of early tumor shrinkage (ETS), tumor location, and VEGF-D with progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox proportional hazards model. Spearman's correlation coefficient was used to analyze the association of depth of response (DpR) with PFS and OS. Serum VEGF-D levels were measured in samples collected before treatment using magnetic bead panel Milliplex xMAP kits. RESULTS In total, 101 patients (Pani, n = 49; Bev, n = 52) were enrolled in this study. Patients with ETS had longer PFS (Pani: hazard ratio (HR) 0.40, P = 0.009; Bev: HR 0.078, P = 0.0002) and OS (Pani: HR 0.49, P = 0.044; Bev: HR 0.35, P = 0.048) than patients without ETS. The DpR was moderately correlated with PFS and OS in Pani (rs = 0.75, P < 0.001; rs = 0.60, P < 0.001) and Bev groups (rs = 0.68, P < 0.001; rs = 0.44, P = 0.002). No significant differences were observed in PFS and OS between the two treatment groups even if in left-sided tumors. No significant interaction between VEGF-D levels and treatment was observed in PFS and OS. CONCLUSIONS ETS and DpR serve as surrogate markers of PFS and OS in the second-line treatment with FOLFIRI plus targeted agent for mCRC.
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Affiliation(s)
- Naoki Izawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kimio Yonesaka
- Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-sayama, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Tadamichi Denda
- Department of Gastroenterology, Chiba Cancer Center Hospital, Chiba, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shimonagakubo, Japan
| | - Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Hiroyuki Okuda
- Department of Medical Oncology, Keiyukai Sapporo Hospital, Sapporo, Japan
| | - Chihiro Kondoh
- Department of Medical Oncology, Toranomon Hospital, Tokyo, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Akitaka Makiyama
- Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Kita-Kyushu, Japan
- Cancer Center, Gifu University Hospital, Gifu, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hironori Yamaguchi
- Department of Gastrointestinal Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Masato Nakamura
- Aizawa Comprehensive Cancer Center, Aizawa Hospital, Matsumoto, Japan
| | - Ichinosuke Hyodo
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Takako Eguchi Nakajima
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
- Kyoto Innovation Center for Next Generation Clinical Trials and iPS Cell Therapy (Ki-CONNECT), Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
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31
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Moradi A, Pourseif MM, Jafari B, Parvizpour S, Omidi Y. Nanobody-based therapeutics against colorectal cancer: Precision therapies based on the personal mutanome profile and tumor neoantigens. Pharmacol Res 2020; 156:104790. [DOI: 10.1016/j.phrs.2020.104790] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/19/2022]
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Wu W, Zhou G, Han H, Huang X, Jiang H, Mukai S, Kazlauskas A, Cui J, Matsubara JA, Vanhaesebroeck B, Xia X, Wang J, Lei H. PI3Kδ as a Novel Therapeutic Target in Pathological Angiogenesis. Diabetes 2020; 69:736-748. [PMID: 31915155 PMCID: PMC7085248 DOI: 10.2337/db19-0713] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Accepted: 12/25/2019] [Indexed: 12/12/2022]
Abstract
Diabetic retinopathy is the most common microvascular complication of diabetes, and in the advanced diabetic retinopathy appear vitreal fibrovascular membranes that consist of a variety of cells, including vascular endothelial cells (ECs). New therapeutic approaches for this diabetic complication are urgently needed. Here, we report that in cultured human retinal microvascular ECs, high glucose induced expression of p110δ, which was also expressed in ECs of fibrovascular membranes from patients with diabetes. This catalytic subunit of a receptor-regulated PI3K isoform δ is known to be highly enriched in leukocytes. Using genetic and pharmacological approaches, we show that p110δ activity in cultured ECs controls Akt activation, cell proliferation, migration, and tube formation induced by vascular endothelial growth factor, basic fibroblast growth factor, and epidermal growth factor. Using a mouse model of oxygen-induced retinopathy, p110δ inactivation was found to attenuate pathological retinal angiogenesis. p110δ inhibitors have been approved for use in human B-cell malignancies. Our data suggest that antagonizing p110δ constitutes a previously unappreciated therapeutic opportunity for diabetic retinopathy.
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Affiliation(s)
- Wenyi Wu
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
- Schepens Eye Research Institute of Massachusetts Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Guohong Zhou
- Schepens Eye Research Institute of Massachusetts Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, MA
- Shanxi Eye Hospital, Taiyuan, China
| | - Haote Han
- Schepens Eye Research Institute of Massachusetts Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Xionggao Huang
- Schepens Eye Research Institute of Massachusetts Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, MA
- Department of Ophthalmology, the First Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Heng Jiang
- Schepens Eye Research Institute of Massachusetts Eye and Ear and Department of Ophthalmology, Harvard Medical School, Boston, MA
- Department of Ophthalmology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Shizuo Mukai
- Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA
| | - Andrius Kazlauskas
- Department of Ophthalmology and Visual Sciences and Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL
| | - Jing Cui
- The University of British Columbia, Vancouver, British Columbia, Canada
| | | | | | - Xiaobo Xia
- Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
| | - Jiantao Wang
- Shenzhen Eye Hospital, Shenzhen Eye Institute, Shenzhen, China
| | - Hetian Lei
- Shenzhen Eye Hospital, Shenzhen Eye Institute, Shenzhen, China
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Jana P, Acharya K. Mushroom: A New Resource for Anti-Angiogenic Therapeutics. FOOD REVIEWS INTERNATIONAL 2020. [DOI: 10.1080/87559129.2020.1721529] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Affiliation(s)
- Pradipta Jana
- Molecular and Applied Mycology and Pathology Laboratory, Department of Botany, University of Calcutta, Calcutta, India
| | - Krishnendu Acharya
- Molecular and Applied Mycology and Pathology Laboratory, Department of Botany, University of Calcutta, Calcutta, India
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HB-EGF-EGFR Signaling in Bone Marrow Endothelial Cells Mediates Angiogenesis Associated with Multiple Myeloma. Cancers (Basel) 2020; 12:cancers12010173. [PMID: 31936715 PMCID: PMC7017291 DOI: 10.3390/cancers12010173] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 01/02/2020] [Accepted: 01/08/2020] [Indexed: 12/25/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) and its ligand heparin-binding EGF-like growth factor (HB-EGF) sustain endothelial cell proliferation and angiogenesis in solid tumors, but little is known about the role of HB-EGF–EGFR signaling in bone marrow angiogenesis and multiple myeloma (MM) progression. We found that bone marrow endothelial cells from patients with MM express high levels of EGFR and HB-EGF, compared with cells from patients with monoclonal gammopathy of undetermined significance, and that overexpressed HB-EGF stimulates EGFR expression in an autocrine loop. We also found that levels of EGFR and HB-EGF parallel MM plasma cell number, and that HB-EGF is a potent inducer of angiogenesis in vitro and in vivo. Moreover, blockade of HB-EGF–EGFR signaling, by an anti-HB-EGF neutralizing antibody or the EGFR inhibitor erlotinib, limited the angiogenic potential of bone marrow endothelial cells and hampered tumor growth in an MM xenograft mouse model. These results identify HB-EGF–EGFR signaling as a potential target of anti-angiogenic therapy, and encourage the clinical investigation of EGFR inhibitors in combination with conventional cytotoxic drugs as a new therapeutic strategy for MM.
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Zhang Z, Luo F, Zhang Y, Ma Y, Hong S, Yang Y, Fang W, Huang Y, Zhang L, Zhao H. The ACTIVE study protocol: apatinib or placebo plus gefitinib as first-line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (CTONG1706). Cancer Commun (Lond) 2019; 39:69. [PMID: 31699150 PMCID: PMC6839103 DOI: 10.1186/s40880-019-0414-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Accepted: 10/22/2019] [Indexed: 12/31/2022] Open
Abstract
Background Gefitinib, as the first epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC), has been proved to significantly improve the progression-free survival (PFS) in the first-line setting but suffers from resistance 7–10 months after treatment initiation. Apatinib (YN968D1), a potent vascular endothelial growth factor receptor (VEGFR) 2-TKI, specifically binds to VEGFR2 and leads to anti-angiogenetic and anti-neoplastic effect. Concurrent inhibition of VEGFR and EGFR pathways represents a rational approach to improve treatment responses and delay the onset of treatment resistance in EGFR-mutant NSCLC. This ACTIVE study aims to assess the combination of apatinib and gefitinib as a new treatment approach for EGFR-mutant NSCLC as a first-line setting. Methods This multicenter, randomized, double-blind, placebo-controlled phase III study (NCT02824458) has been designed to assess the efficacy and safety of apatinib or placebo combined with gefitinib as a first-line treatment for patients with EGFR-mutant advanced NSCLC. A total of 310 patients with EGFR-mutation (19del or 21L858R), pathological stage IIIB to IV non-squamous NSCLC were to be enrolled. The primary endpoint is investigator assessment of PFS, and the secondary endpoints include independent radiological central (IRC)-confirmed PFS, overall survival (OS), objective response rate (ORR), disease control rate (DCR), time to progressive disease (TTPD), duration of response (DoR), quality of life (QoL) and safety. The patients are randomized in a 1:1 ratio to receive gefitinib (250 mg, p.o. q.d.) plus apatinib (500 mg, p.o. q.d.) or gefitinib plus placebo, given until disease progression or intolerable adverse events. Exploratory biomarker analysis will be performed. This study is being conducted across China and comprises of 30 participating centers. Enrollment commenced in August 2017 and finished in December 2018, most of the patients are in the follow-up period. Anticipated outcomes and significance The present study will be the first to evaluate the efficacy and safety profile of the combination of apatinib plus gefitinib as a first-line therapy for patients with EGFR-positive advanced non-squamous NSCLC. Importantly, this trial will provide comprehensive evidence on the treatment of EGFR-TKIs combined with antiangiogenic therapy. Trial registration Clinicaltrials.gov NCT02824458. Registered 23 June 2016
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Affiliation(s)
- Zhonghan Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Fan Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Yang Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.,Department of Clinical Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Yuxiang Ma
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.,Department of Clinical Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Shaodong Hong
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Yunpeng Yang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Wenfeng Fang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Yan Huang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China.,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China
| | - Li Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. .,Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China.
| | - Hongyun Zhao
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, P. R. China. .,Department of Clinical Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P. R. China.
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Zhang J, Song Y, Liang Y, Zou H, Zuo P, Yan M, Jing S, Li T, Wang Y, Li D, Zhang T, Wei Z. Cucurbitacin IIa interferes with EGFR-MAPK signaling pathway leads to proliferation inhibition in A549 cells. Food Chem Toxicol 2019; 132:110654. [DOI: 10.1016/j.fct.2019.110654] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Revised: 06/25/2019] [Accepted: 06/29/2019] [Indexed: 12/20/2022]
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Schmohl KA, Nelson PJ, Spitzweg C. Tetrac as an anti-angiogenic agent in cancer. Endocr Relat Cancer 2019; 26:R287-R304. [PMID: 31063970 DOI: 10.1530/erc-19-0058] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 04/04/2019] [Indexed: 12/24/2022]
Abstract
The thyroid hormones T3 and T4 have emerged as pro-angiogenic hormones with important implications for cancer management. Endogenous circulating hormone levels may help stimulate cancer progression and limit the effectiveness of anticancer therapy, though clinical data remain inconclusive. The capacity of thyroid hormones to modulate angiogenesis is mediated through non-canonical mechanisms initiated at the cell surface receptor integrin αvβ3. This integrin is predominantly expressed on tumour cells, proliferating endothelial cells and tumour stroma-associated cells, emphasising its potential relevance in angiogenesis and tumour biology. Thyroid hormone/integrin αvβ3 signalling results in the activation of intracellular pathways that are commonly associated with angiogenesis and are mediated through classical pro-angiogenic molecules such as vascular endothelial growth factor. The naturally occurring T4 analogue tetrac blocks the pro-angiogenic actions of thyroid hormones at the integrin receptor, in addition to agonist-independent anti-angiogenic effects. Tetrac reduces endothelial cell proliferation, migration and tube formation through a reduction in the transcription of vascular growth factors/growth factor receptors, hypoxia-inducible factor-1α, pro-angiogenic cytokines and a number of other pro-angiogenic genes, while at the same time stimulating the expression of endogenous angiogenesis inhibitors. It further modulates vascular growth factor activity by disrupting the crosstalk between integrin αvβ3 and adjacent growth factor receptors. Moreover, tetrac disrupts thyroid hormone-stimulated tumour recruitment, differentiation and the pro-angiogenic signalling of tumour stroma-associated mesenchymal stem cells. Tetrac affects tumour-associated angiogenesis via multiple mechanisms and interferes with other cancer cell survival pathways. In conjunction with its low toxicity and high tissue selectivity, tetrac is a promising candidate for clinical application.
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Affiliation(s)
- Kathrin A Schmohl
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Peter J Nelson
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
| | - Christine Spitzweg
- Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany
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Effect of Cetuximab on the Development of Epidural Fibrosis Based on CD105 and Osteopontin Immunohistochemical Staining. Spine (Phila Pa 1976) 2019; 44:E134-E143. [PMID: 30015719 DOI: 10.1097/brs.0000000000002793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN The effect of cetuximab on the development of epidural fibrosis (EF) was assessed using immunohistochemical methods as well as antibodies for CD105 and osteopontin (OPN). OBJECTIVE The goal of this study was to assess of EGFR inhibition for the postoperative treatment of fibrosis. SUMMARY OF BACKGROUND DATA EF is one of most common causes of failed back surgery syndrome, which occurs after laminectomy. Numerous causes and mechanisms have been proposed to explain its development after laminectomy. Many agents have been tested to prevent the development of EF. EGFR, a multi-functional transmembrane glycoprotein, causes cell growth, proliferation, and EF by interacting with epidermal growth factor and TGF-β1. The inhibition of postoperative fibrosis using cetuximab, an epidermal growth factor receptor blocker, is theoretically possible. However, this has not been tested to date. METHODS Sixteen Wistar-Albino rats were divided into two groups, namely, control and cetuximab groups. L1-2 laminectomy alone was performed in both groups, and topical cetuximab was applied to the treatment group. After 6 weeks, rats were sacrificed and examined histopathologically and immunohistochemically; EF tissue was also graded. Statistical significance was accepted at P < 0.05. RESULTS Fibroblast counts and fibrosis density, determined by histopathologic examination, and EF, according to immunohistochemical assessment based on CD105, were found to be higher in the treatment group than in the control group, and this was statistically significant (P < 0.001). Based on OPN staining, the results were consistent with classical methods, and no significant difference was detected among the groups (P = 0.358). CONCLUSION Our study revealed that cetuximab inhibits the development of EF and that CD105, and not OPN, is a reliable marker for grading EF. In addition, cetuximab did not result in toxic, systemic side effects in surrounding tissues. LEVEL OF EVIDENCE N/A.
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Liu Q, Yu S, Zhao W, Qin S, Chu Q, Wu K. EGFR-TKIs resistance via EGFR-independent signaling pathways. Mol Cancer 2018; 17:53. [PMID: 29455669 PMCID: PMC5817859 DOI: 10.1186/s12943-018-0793-1] [Citation(s) in RCA: 246] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 02/01/2018] [Indexed: 01/29/2023] Open
Abstract
Tyrosine kinase inhibitors (TKIs)-treatments bring significant benefit for patients harboring epidermal growth factor receptor (EGFR) mutations, especially for those with lung cancer. Unfortunately, the majority of these patients ultimately develop to the acquired resistance after a period of treatment. Two central mechanisms are involved in the resistant process: EGFR secondary mutations and bypass signaling activations. In an EGFR-dependent manner, acquired mutations, such as T790 M, interferes the interaction between TKIs and the kinase domain of EGFR. While in an EGFR-independent manner, dysregulation of other receptor tyrosine kinases (RTKs) or abnormal activation of downstream compounds both have compensatory functions against the inhibition of EGFR through triggering phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling axes. Nowadays, many clinical trials aiming to overcome and prevent TKIs resistance in various cancers are ongoing or completed. EGFR-TKIs in accompany with the targeted agents for resistance-related factors afford a promising first-line strategy to further clinical application.
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Affiliation(s)
- Qian Liu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shengnan Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Weiheng Zhao
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shuang Qin
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Arezumand R, Alibakhshi A, Ranjbari J, Ramazani A, Muyldermans S. Nanobodies As Novel Agents for Targeting Angiogenesis in Solid Cancers. Front Immunol 2017; 8:1746. [PMID: 29276515 PMCID: PMC5727022 DOI: 10.3389/fimmu.2017.01746] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 11/23/2017] [Indexed: 12/20/2022] Open
Abstract
Solid cancers are dependent on angiogenesis for sustenance. The FDA approval of Bevacizumab in 2004 inspired many scientists to develop more inhibitors of angiogenesis. Although several monoclonal antibodies (mAbs) are being administered to successfully combat various pathologies, the complexity and large size of mAbs seem to narrow the therapeutic applications. To improve the performance of cancer therapeutics, including those blocking tumor angiogenesis, attractive strategies such as miniaturization of the antibodies have been introduced. Nanobodies (Nbs), small single-domain antigen-binding antibody fragments, are becoming promising therapeutic and diagnostic proteins in oncology due to their favorable unique structural and functional properties. This review focuses on the potential and state of the art of Nbs to inhibit the angiogenic process for therapy and the use of labeled Nbs for non-invasive in vivo imaging of the tumors.
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Affiliation(s)
- Roghaye Arezumand
- Department of Biotechnology and Molecular Science, School of Medicine, North Khorasan University of Medical Sciences, Bojnourd, Iran
| | - Abbas Alibakhshi
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Javad Ranjbari
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Ramazani
- Cancer Gene Therapy Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Serge Muyldermans
- Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
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Xu J, Liu X, Yang S, Zhang X, Shi Y. Apatinib plus icotinib in treating advanced non-small cell lung cancer after icotinib treatment failure: a retrospective study. Onco Targets Ther 2017; 10:4989-4995. [PMID: 29075129 PMCID: PMC5648303 DOI: 10.2147/ott.s142686] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Background Treatment failure frequently occurs in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) who respond to EGFR tyrosine kinase inhibitors initially. This retrospective study tried to investigate the efficacy and safety of apatinib plus icotinib in patients with advanced NSCLC after icotinib treatment failure. Patients and methods This study comprised 27 patients with advanced NSCLC who had progressed after icotinib monotherapy. Initially, patients received oral icotinib (125 mg, tid) alone. When the disease progressed, they received icotinib plus apatinib (500 mg, qd, orally). Treatment was continued until disease progression, unacceptable toxicity or consent withdrawal. Results Followed up to December 2016, the median time of combined therapy was 7.47 months, and eight of 27 patients were dead. The median overall survival was not reached, and median progression-free survival (PFS) was 5.33 months (95% CI, 3.63–7.03 months). Moreover, the objective response rate (ORR) was 11.1%, and the disease control rate (DCR) was 81.5%. A total of 14 patients received combined therapy as the second-line treatment, and the ORR and DCR were 7.1% and 78.6%, respectively; 13 patients received drugs as the third- or later-line treatment, with an ORR and a DCR of 15.4% and 84.6%, respectively. In addition, 11 patients experienced icotinib monotherapy failure within 6 months with median PFS of 7.37 months, and 16 patients had progression after 6 months with median PFS of 2.60 months. The common drug-related toxic effects were hypertension (44.4%) and fatigue (37.0%). Conclusion Apatinib plus icotinib is efficacious in treating patients with advanced NSCLC after icotinib treatment failure, with acceptable toxic effects.
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Affiliation(s)
- Jianping Xu
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China
| | - Xiaoyan Liu
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China
| | - Sheng Yang
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China
| | - Xiangru Zhang
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China
| | - Yuankai Shi
- Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, People's Republic of China
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Carrasco P, Zuazo-Gaztelu I, Casanovas O. Sprouting strategies and dead ends in anti-angiogenic targeting of NETs. J Mol Endocrinol 2017; 59:R77-R91. [PMID: 28469004 DOI: 10.1530/jme-17-0029] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Accepted: 05/03/2017] [Indexed: 01/13/2023]
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that arise from cells of the neuroendocrine system. NETs are characterized by being highly vascularized tumors that produce large amounts of proangiogenic factors. Due to their complexity and heterogeneity, progress in the development of successful therapeutic approaches has been limited. For instance, standard chemotherapy-based therapies have proven to be poorly selective for tumor cells and toxic for normal tissues. Considering the urge to develop an efficient therapy to treat NET patients, vascular targeting has been proposed as a new approach to block tumor growth. This review provides an update of the mechanisms regulating different components of vessels and their contribution to tumor progression in order to develop new therapeutic drugs. Following the description of classical anti-angiogenic therapies that target VEGF pathway, new angiogenic targets such as PDGFs, EGFs, FGFs and semaphorins are further explored. Based on recent research in the field, the combination of therapies that target multiple and different components of vessel formation would be the best approach to specifically target NETs and inhibit tumor growth.
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Affiliation(s)
- Patricia Carrasco
- Tumor Angiogenesis GroupProCURE, Catalan Institute of Oncology - IDIBELL, Barcelona, Spain
| | - Iratxe Zuazo-Gaztelu
- Tumor Angiogenesis GroupProCURE, Catalan Institute of Oncology - IDIBELL, Barcelona, Spain
| | - Oriol Casanovas
- Tumor Angiogenesis GroupProCURE, Catalan Institute of Oncology - IDIBELL, Barcelona, Spain
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Hashemi Goradel N, Ghiyami-Hour F, Jahangiri S, Negahdari B, Sahebkar A, Masoudifar A, Mirzaei H. Nanoparticles as new tools for inhibition of cancer angiogenesis. J Cell Physiol 2017; 233:2902-2910. [PMID: 28543172 DOI: 10.1002/jcp.26029] [Citation(s) in RCA: 128] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 05/24/2017] [Indexed: 12/14/2022]
Abstract
Angiogenesis is known as one of the hallmarks of cancer. Multiple lines evidence indicated that vascular endothelium growth factor (VEGF) is a key player in the progression of angiogenesis and exerts its functions via interaction with tyrosine kinase receptors (TKRs). These receptors could trigger a variety of cascades that lead to the supply of oxygen and nutrients to tumor cells and survival of these cells. With respect to pivotal role of angiogenesis in the tumor growth and survival, finding new therapeutic approaches via targeting angiogenesis could open a new horizon in cancer therapy. Among various types of therapeutic strategies, nanotechnology has emerged as new approach for the treatment of various cancers. Nanoparticles (NPs) could be used as effective tools for targeting a variety of therapeutic agents. According to in vitro and in vivo studies, NPs are efficient in depriving tumor cells from nutrients and oxygen by inhibiting angiogenesis. However, the utilization of NPs are associated with a variety of limitations. It seems that new approaches such as NPs conjugated with hydrogels could overcome to some limitations. In the present review, we summarize various mechanisms involved in angiogenesis, common anti-angiogenesis strategies, and application of NPs for targeting angiogenesis in various cancers.
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Affiliation(s)
- Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Farshid Ghiyami-Hour
- Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Jahangiri
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Babak Negahdari
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Aria Masoudifar
- Department of Molecular Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan, Iran
| | - Hamed Mirzaei
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Derangère V, Fumet JD, Boidot R, Bengrine L, Limagne E, Chevriaux A, Vincent J, Ladoire S, Apetoh L, Rébé C, Ghiringhelli F. Does bevacizumab impact anti-EGFR therapy efficacy in metastatic colorectal cancer? Oncotarget 2017; 7:9309-21. [PMID: 26824184 PMCID: PMC4891042 DOI: 10.18632/oncotarget.7008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 01/01/2016] [Indexed: 12/15/2022] Open
Abstract
Anti-EGFR therapy and antiangiogenic therapies are used alone or in combination with chemotherapies to improve survival in metastatic colorectal cancer. However, it is unknown whether pretreatment with antiangiogenic therapy could impact on the efficacy of anti-EGFR therapy. We selected one hundred and twenty eight patients diagnosed with advanced colorectal cancer with a KRAS and NRAS unmutated tumor. These patients were treated with cetuximab or panitumumab alone or with chemotherapy as second or third-line. Univariate and multivariate Cox model analysis were performed to estimate the effect of a previous bevacizumab regimen on progression free survival and on overall survival during anti-EGFR therapy. In vitro studies using wild type KRAS and NRAS colon cancer cells were performed to evaluate the impact of VEGF-A on cetuximab-induced cell death. The median progression free survival (PFS) during anti-EGFR treatment was significantly different between the bevacizumab group and the non-bevacizumab group (2.8 and 4 months respectively; p = 0.003). The median overall survival from the beginning of the metastatic disease was similar in the two groups (41.3 and 42 months respectively; p = 0.7). In vitro, VEGF-A induced a resistance toward cetuximab cytotoxicity on three KRAS and NRAS wild type colon cancer cell lines in a VEGFR2 and Stat-3-dependent manner. All in all, our clinical data, supported by in vitro procedures, suggest that a previous anti-VEGF therapy decreases anti-EGFR efficacy. Although these results are observed in a limited cohort, they could be taken into consideration for a better strategy of care for patient suffering from metastatic colorectal cancer.
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Affiliation(s)
- Valentin Derangère
- INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France
| | | | | | | | - Emeric Limagne
- INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France
| | - Angélique Chevriaux
- INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.,Centre Georges-François Leclerc, Dijon, France
| | | | - Sylvain Ladoire
- INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.,Centre Georges-François Leclerc, Dijon, France
| | - Lionel Apetoh
- INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France
| | - Cédric Rébé
- INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.,Centre Georges-François Leclerc, Dijon, France
| | - François Ghiringhelli
- INSERM, U866, Faculté de Médecine, Université de Bourgogne, Dijon, France.,Centre Georges-François Leclerc, Dijon, France
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Ding C, Li L, Yang T, Fan X, Wu G. Combined application of anti-VEGF and anti-EGFR attenuates the growth and angiogenesis of colorectal cancer mainly through suppressing AKT and ERK signaling in mice model. BMC Cancer 2016; 16:791. [PMID: 27729020 PMCID: PMC5059930 DOI: 10.1186/s12885-016-2834-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 10/05/2016] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Angiogenesis is generally involved during the cancer development and hematogenous metastasis. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are considered to have an important role in tumor-associated angiogenesis. However, the effects of simultaneously targeting on VEGF and EGFR on the growth and angiogenesis of colorectal cancer (CRC), and its underlying mechanisms remain unknown. METHODS Immunohistochemical staining was used to detect the VEGF and EGFR expression in different CRC tissue specimens, and the correlation between VEGF/EGFR expression with the clinicopathologic features was analyzed. Cell counting kit‑8 (CCK-8) and transwell assays were used to assess the cellular proliferation and invasion of CRC cells after treated with anti-VEGF antibody and/or anti-EGFR antibody in vitro, respectively. Moreover, in vivo tumor formation was performed on nude mice model, and the tumor microvessel density (MVD) was determined by anti-CD34 staining in different groups. Finally, we evaluated the impact of anti-VEGF antibody and/or anti-EGFR antibody on the activation of downstream signaling effectors using western blot. RESULTS VEGF and EGFR were upregulated in CRC tissues, and their expression levels were correlated with hepatic metastasis. Blockage on VEGF or EGFR alone could inhibit the cellular proliferation and metastasis while their combination could reach a good synergism in vitro. In addition, in vivo xenograft mice model demonstrated that the tumor formation and angiogenesis were strongly suppressed by combination treatment of anti-VEGF and anti-EGFR antibodies. Besides, the combination treatment significantly reduced the activation of AKT and ERK1/2, but barely affected the activation of c-Myc, NF-κB/p65 and IκBα in CRC cells tumors. Interestingly, anti-VEGF antibody or anti-EGFR antibody alone could attenuate the phosphorylation of STAT3 as compared with negative control group, whereas the combined application not further suppressed but at least partially restored the activation of STAT3 in vivo. CONCLUSIONS Simultaneous targeting on VEGF and EGFR does show significant inhibition on CRC tumor growth and angiogenesis in mice model, and these effects are mainly attributed to suppression of the AKT and ERK signaling pathways.
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Affiliation(s)
- Chenbo Ding
- Medical School of Southeast University, Nanjing, 210009, China
| | - Longmei Li
- Department of Immunology, Zunyi Medical University, Zunyi, 563003, China
| | - Taoyu Yang
- Department of Oncology, the Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, China
| | - Xiaobo Fan
- Medical School of Southeast University, Nanjing, 210009, China
| | - Guoqiu Wu
- Medical School of Southeast University, Nanjing, 210009, China. .,Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
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Biel NM, Siemann DW. Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference. Cancer Lett 2016; 380:525-533. [PMID: 25312939 PMCID: PMC4394020 DOI: 10.1016/j.canlet.2014.09.035] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 09/11/2014] [Accepted: 09/30/2014] [Indexed: 12/13/2022]
Abstract
Anti-angiogenic therapies target the tumor vasculature, impairing its development and growth. It was hypothesized over 40 years ago by the late Judah Folkman and Julie Denekamp that depriving a tumor of oxygen and nutrients, by targeting the tumor vasculature, could have therapeutic benefits. Identification of growth factors and signaling pathways important in angiogenesis subsequently led to the development of a series of anti-angiogenic agents that over the past decade have become part of the standard of care in several disease settings. Unfortunately not all patients respond to the currently available anti-angiogenic therapies while others become resistant to these agents following prolonged exposure. Identification of new pathways that may drive angiogenesis led to the development of second-generation anti-angiogenic agents such as those targeting the Ang-2/Tie2 axis. Recently, it has become clear that combination of first and second generation agents targeting the blood vessel network can lead to outcomes superior to those using either agent alone. The present review focuses on the current status of VEGF and Ang-2 targeted agents and the potential utility of using them in combination to impair tumor angiogenesis.
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Affiliation(s)
- Nikolett M Biel
- Department of Pathology, University of Florida College of Medicine, 1395 Center Drive, Gainesville, FL 32610, USA.
| | - Dietmar W Siemann
- Department of Radiation Oncology, University of Florida College of Medicine, 2000 SW, Archer Road, Gainesville, FL 32610, USA
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Minder P, Zajac E, Quigley JP, Deryugina EI. EGFR regulates the development and microarchitecture of intratumoral angiogenic vasculature capable of sustaining cancer cell intravasation. Neoplasia 2016; 17:634-49. [PMID: 26408256 PMCID: PMC4674488 DOI: 10.1016/j.neo.2015.08.002] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 07/28/2015] [Accepted: 08/10/2015] [Indexed: 12/16/2022] Open
Abstract
Many malignant characteristics of cancer cells are regulated through pathways induced by the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Herein, we show that besides directly affecting the biology of cancer cells per se, EGFR also regulates the primary tumor microenvironment. Specifically, our findings demonstrate that both the expression and signaling activity of EGFR are required for the induction of a distinct intratumoral vasculature capable of sustaining tumor cell intravasation, a critical rate-limiting step in the metastatic cascade. An intravasation-sustaining mode of intratumoral angiogenic vessels depends on high levels of tumor cell EGFR and the interplay between EGFR-regulated production of interleukin 8 by tumor cells, interleukin-8–induced influx of tumor-infiltrating neutrophils delivering their unique matrix metalloproteinase-9, and neutrophil matrix metalloproteinase-9–dependent release of the vascular permeability and endothelial growth factor, VEGF. Our data indicate that through VEGF-mediated disruption of endothelial layer integrity and increase of intratumoral vasculature permeability, EGFR activity significantly facilitates active intravasation of cancer cells. Therefore, this study unraveled an important but overlooked function of EGFR in cancer, namely, its ability to create an intravasation-sustaining microenvironment within the developing primary tumor by orchestrating several interrelated processes required for the initial steps of cancer metastasis through vascular routes. Our findings also suggest that EGFR-targeted therapies might be more effective when implemented in cancer patients with early-staged primary tumors containing a VEGF-dependent angiogenic vasculature. Accordingly, early EGFR inhibition combined with various anti-VEGF approaches could synergistically suppress tumor cell intravasation through inhibiting the highly permeable angiogenic vasculature induced by EGFR-overexpressing aggressive cancer cells.
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Affiliation(s)
- Petra Minder
- The Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
| | - Ewa Zajac
- The Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
| | - James P Quigley
- The Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA
| | - Elena I Deryugina
- The Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, CA.
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Brown N, McBain C, Nash S, Hopkins K, Sanghera P, Saran F, Phillips M, Dungey F, Clifton-Hadley L, Wanek K, Krell D, Jeffries S, Khan I, Smith P, Mulholland P. Multi-Center Randomized Phase II Study Comparing Cediranib plus Gefitinib with Cediranib plus Placebo in Subjects with Recurrent/Progressive Glioblastoma. PLoS One 2016; 11:e0156369. [PMID: 27232884 PMCID: PMC4883746 DOI: 10.1371/journal.pone.0156369] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 05/12/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, failed to show benefit over lomustine in relapsed glioblastoma. One resistance mechanism for cediranib is up-regulation of epidermal growth factor receptor (EGFR). This study aimed to determine if dual therapy with cediranib and the oral EGFR inhibitor gefitinib improved outcome in recurrent glioblastoma. METHODS AND FINDINGS This was a multi-center randomized, two-armed, double-blinded phase II study comparing cediranib plus gefitinib versus cediranib plus placebo in subjects with first relapse/first progression of glioblastoma following surgery and chemoradiotherapy. The primary outcome measure was progression free survival (PFS). Secondary outcome measures included overall survival (OS) and radiologic response rate. Recruitment was terminated early following suspension of the cediranib program. 38 subjects (112 planned) were enrolled with 19 subjects in each treatment arm. Median PFS with cediranib plus gefitinib was 3.6 months compared to 2.8 months for cediranib plus placebo (HR; 0.72, 90% CI; 0.41 to 1.26). Median OS was 7.2 months with cediranib plus gefitinib and 5.5 months with cediranib plus placebo (HR; 0.68, 90% CI; 0.39 to 1.19). Eight subjects (42%) had a partial response in the cediranib plus gefitinib arm versus five patients (26%) in the cediranib plus placebo arm. CONCLUSIONS Cediranib and gefitinib in combination is tolerated in patients with glioblastoma. Incomplete recruitment led to the study being underpowered. However, a trend towards improved survival and response rates with the addition of gefitinib to cediranib was observed. Further studies of the combination incorporating EGFR and VEGF inhibition are warranted. TRIAL REGISTRATION ClinicalTrials.gov NCT01310855.
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Affiliation(s)
- Nicholas Brown
- University College London Hospitals, London, United Kingdom
| | | | - Stephen Nash
- Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom
| | - Kirsten Hopkins
- Bristol Haematology and Oncology Centre, Bristol, United Kingdom
| | - Paul Sanghera
- Hall Edwards Radiotherapy Research Group, University Hospital Birmingham, Birmingham, United Kingdom
| | - Frank Saran
- Department of Radiotherapy and Paediatric Oncology, Royal Marsden NHS Trust, Sutton, United Kingdom
| | - Mark Phillips
- Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom
| | - Fiona Dungey
- Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom
| | | | - Katharina Wanek
- Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom
| | - Daniel Krell
- Department of Academic Oncology, Royal Free Hospital, London, United Kingdom
| | - Sarah Jeffries
- Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom
| | - Iftekhar Khan
- Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom
| | - Paul Smith
- Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom
| | - Paul Mulholland
- UCL Cancer Institute, University College London, London, United Kingdom
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Kang HN, Kim SH, Yun MR, Kim HR, Lim SM, Kim MS, Hong KW, Kim SM, Kim H, Pyo KH, Park HJ, Han JY, Youn HA, Chang KH, Cho BC. ER2, a novel human anti-EGFR monoclonal antibody inhibit tumor activity in non-small cell lung cancer models. Lung Cancer 2016; 95:57-64. [DOI: 10.1016/j.lungcan.2016.02.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Revised: 01/29/2016] [Accepted: 02/24/2016] [Indexed: 12/16/2022]
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Takahashi N, Iwasa S, Taniguchi H, Sasaki Y, Shoji H, Honma Y, Takashima A, Okita N, Kato K, Hamaguchi T, Shimada Y, Yamada Y. Prognostic role of ERBB2, MET and VEGFA expression in metastatic colorectal cancer patients treated with anti-EGFR antibodies. Br J Cancer 2016; 114:1003-11. [PMID: 27002940 PMCID: PMC4984915 DOI: 10.1038/bjc.2016.74] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/06/2016] [Accepted: 02/17/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND High amplification of epiregulin (EREG) and amphireglin (AREG) in tumour tissues has been previously reported to be associated with better outcome in metastatic colorectal cancer (mCRC) patients who were treated with anti-EGFR antibodies. Here we investigated associations between the expression of other candidate prognostic biomarkers and outcome in mCRC patients receiving similar treatment. METHODS The relative mRNA levels of seven genes including ERBB2, MET, VEGFA, EREG, AREG, PTEN and ERCC1 between tumour (T) and non-tumour (NT) tissue sections were analysed by quantitative real-time PCR. Relative mRNA values, that is, T/NT ratios, of target genes were calculated and hazard ratios (HRs) for each gene of interest were adjusted for age, gender, performance status, minor RAS mutations and other clinicopathological variables which exhibited P-values<0.1 on the basis of univariate analysis. RESULTS Among 108 cases who received anti-EGFR antibodies, there were 96 cases of KRAS exon2 wild-type patients enroled in this study. When the cutoff values for relative mRNA levels were set to the upper 25th percentile of all patients, there were statistically significant differences in overall survival (OS) between the patients with high and low levels of EREG (HR: 0.326, 95% CI: 0.136-0.772, P=0.011), ERBB2 (HR: 1.31, 95% CI: 1.084-1.652, P=0.040), MET (HR: 2.48, 95% CI: 1.356-5.463, P=0.026), and VEGF-A (HR: 1.29, 95% CI: 1.036-1.606, P=0.046). In addition, patients with high ERBB2 had shorter progression-free survival (PFS) compared with low ERBB2 (HR: 1.98, 95% CI: 1.062-3.850). There were no significant differences in PFS and OS with respect to relative expression levels of PTEN and ERCC1. The prognostic role of AREG was evaluated in only T sections, as the mRNA expression level of this gene was mostly (91% cases) undetectable in NT sections. Patients with high AREG had longer OS compared with low AREG (HR: 0.227, 95% CI: 0.095-0.808). CONCLUSIONS Our study has shown that higher T/NT ratios of ERBB2, MET and VEGFA mRNA were associated with worse OS in mCRC patients treated with anti-EGFR antibodies, with higher EREG and AREG were associated with better prognosis in the same setting. These findings will contribute the further understanding and management of anti-EGFR antibody treatment in mCRC patients.
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Affiliation(s)
- Naoki Takahashi
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Satoru Iwasa
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hirokazu Taniguchi
- Pathology and Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yusuke Sasaki
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hirokazu Shoji
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yoshitaka Honma
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Atsuo Takashima
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Natsuko Okita
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Ken Kato
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tetsuya Hamaguchi
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yasuhiro Shimada
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yasuhide Yamada
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
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